Dilated cardiomyopathy caused by aberrant endoplasmic reticulum quality control in mutant KDEL receptor transgenic mice
Dilated cardiomyopathy caused by aberrant endoplasmic reticulum quality control in mutant KDEL receptor transgenic mice
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DOI：
10.1128/mcb.24.18.8007-8017.2004
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发表时间：
2004-09-01
影响因子：
5.3
通讯作者：
Aoe, T
中科院分区：
文献类型：
--
作者：
Hamada, H;Suzuki, M;Aoe, T
异常蛋白质折叠超出内质网（ER）质量控制的能力，导致内质网中的应激反应。Lys-Asp-Glu-Leu（KDEL）受体是ER早期分泌途径中伴侣的一种修复受体，有助于ER质量控制。为了阐明KDEL受体在体内的功能，我们建立了表达突变KDEL受体的转基因小鼠。我们发现突变的KDEL受体使细胞对内质网应激敏感，突变小鼠发生扩张型心肌病。超微结构分析显示，扩大的肌浆网和蛋白质聚集体，阻碍了相邻的横小管的突变心肌细胞。突变小鼠的心肌细胞在用衣霉素处理时对ER应激敏感，并且在L型Ca 2+电流中表现出功能缺陷。我们观察到泛素化的蛋白质聚集体，CHOP（ER应激时表达的死亡相关转录因子）的表达增强，以及突变心脏中的细胞凋亡。这些研究结果表明，KDEL受体的损害扰乱ER质量控制，导致错误折叠的蛋白质在体内系统中的ER中的积累，并且在突变KDEL受体转基因小鼠中发现的扩张型心肌病与ER应激相关。
Aberrant protein folding beyond the capacity of endoplasmic reticulum (ER) quality control leads to stress response in the ER. The Lys-Asp-Glu-Leu (KDEL) receptor, a retrieval receptor for ER chaperones in the early secretory pathway, contributes to ER quality control. To elucidate the function of the KDEL receptor in vivo, we established transgenic mice expressing a mutant KDEL receptor. We found that the mutant KDEL receptor sensitized cells to ER stress and that the mutant mice developed dilated cardiomyopathy. Ultrastructural analyses revealed expanded sarcoplasmic reticulums and protein aggregates that obstructed the adjacent transverse tubules of the mutant cardiomyocytes. Cardiomyocytes from the mutant mice were sensitive to ER stress when treated with tunicamycin and showed a functional defect in the L-type Ca2+ current. We observed ubiquitinated protein aggregates, enhanced expression of CHOP (a death-related transcriptional factor expressed upon ER stress), and apoptosis in the mutant hearts. These findings suggest that impairment of the KDEL receptor disturbs ER quality control, resulting in accumulation of misfolded proteins in the ER in an in vivo system, and that the dilated cardiomyopathy found in the mutant KDEL receptor transgenic mice is associated with ER stress.